The emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for the COVID-19 pandemic, prompted a global scientific investigation to trace its origins. Tracing the source of a zoonotic disease—a virus that jumps from animals to humans—is a standard public health response. The initial search focused on bats, the natural reservoir for many coronaviruses, and a potential intermediate species that facilitated the leap to people. Attention soon turned to the pangolin, a reclusive, scaly mammal that is the world’s most heavily trafficked mammal.
Initial Inquiry into Pangolins
The first clusters of human cases in late 2019 were linked to the Huanan Seafood Wholesale Market in Wuhan, China, which sold various live and wild animal products. This market connection raised suspicion, drawing parallels to the 2002 SARS outbreak, where the virus jumped from bats to civets. The search for a similar intermediate host began by examining species commonly sold or trafficked in the region.
Pangolins were an early suspect because they were known to carry coronaviruses, and their illegal trade placed them in high-risk environments for viral transmission. Although their sale was prohibited, scientists soon found coronaviruses in samples from smuggled Malayan pangolins that were genetically related to SARS-CoV-2. This circumstantial evidence, linking a known coronavirus-carrying animal to the wildlife trade, justified a deeper molecular investigation.
Genetic Fingerprint: The Viral Connection
The investigation shifted to molecular biology once pangolin coronaviruses (Pangolin-CoV) were sequenced and compared to SARS-CoV-2. Researchers found that Pangolin-CoV strains shared between 85% and 92.4% overall genetic identity with SARS-CoV-2. While this similarity was substantial, it was not a direct match, suggesting the pangolin virus was not the immediate precursor to the human virus.
The focus narrowed to the Spike (S) protein, the structure that allows the virus to infect host cells. Within the S protein is the Receptor Binding Domain (RBD), which must attach to the human Angiotensin-Converting Enzyme 2 (ACE2) receptor to initiate infection. This domain determines a virus’s ability to jump into a human host. The RBD of the pangolin virus was found to be exceptionally similar to that of SARS-CoV-2.
A comparison of the amino acid residues in this domain revealed a striking finding: five or six key amino acids that enable binding to the human ACE2 receptor were identical between SARS-CoV-2 and the pangolin-CoV. This degree of functional similarity in the RBD was far higher than that found in the closest known bat coronaviruses. This molecular evidence suggested that the pangolin virus possessed a pre-adapted mechanism for infecting human cells. The pangolin became scientifically significant as a potential source for the specific part of the virus that made it a human pathogen.
The Intermediate Host Debate
The genetic data positioned pangolins as a strong candidate for an intermediate host, the species where the virus adapted before jumping to humans. The established theory is that the virus originated in bats, the natural reservoir, and then circulated in another species where it gained the necessary mutations for human transmission. The high-fidelity RBD sequence found in the pangolin virus provided strong evidence for this required adaptation event.
However, the overall genome similarity was not 100%, meaning the exact pangolin coronavirus sequenced was likely not the direct ancestor of the human virus. The overall genetic sequence of SARS-CoV-2 remains closer to a bat coronavirus known as RaTG13. This lack of a perfect match suggests a complex evolutionary pathway, leading to the hypothesis of genetic recombination.
This recombination theory proposes that a bat coronavirus and a pangolin coronavirus co-infected an animal, allowing them to exchange genetic material. The resulting hybrid virus would have inherited the overall backbone from the bat lineage and the highly effective ACE2-binding RBD from the pangolin lineage. The pangolin, therefore, represents a significant evolutionary link, having harbored the specific genetic sequence that enables human infection, even if another animal served as the final link in the chain.
Zoonotic Spillover and Wildlife Trade
The investigation into the pangolin’s role provides a specific example of the broader risks associated with the wildlife trade and zoonotic spillover events. The movement of heavily trafficked wild animals brings them into unnatural proximity with other species and with humans. This mixing creates a high-risk environment where viruses can mutate, recombine, and cross the species barrier.
Pangolins are illegally traded for their meat, considered a delicacy, and their scales, used in traditional medicine. This relentless poaching and transport of live, distressed animals facilitates the exchange of microbes. The conditions of transport and sale in markets, where multiple species are kept in cramped, unsanitary conditions, dramatically increase the likelihood of a virus jumping to a handler or consumer.
Public health experts emphasize that six out of ten known human infectious diseases are zoonotic, and the illegal wildlife trade accelerates this danger. The pangolin case highlights the necessity of strictly regulating wildlife markets and enforcing conservation laws globally. Protecting natural habitats and minimizing human exposure to wild animals are necessary steps to prevent future pandemics originating from similar spillover events.